Object: Reported rates of CSF shunt infection vary widely across studies. The study objective was to determine the CSF shunt infection rates after initial shunt placement at multiple US pediatric hospitals. The authors hypothesized that infection rates between hospitals would vary widely even after adjustment for patient, hospital, and surgeon factors. Methods: This retrospective cohort study included children 0–18 years of age with uncomplicated initial CSF shunt placement performed between January 1, 2001, and December 31, 2005, and recorded in the Pediatric Health Information System (PHIS) longitudinal administrative database from 41 children's hospitals. For each child with 24 months of follow-up, subsequent CSF shunt infections and procedures were determined. Results: The PHIS database included 7071 children with uncomplicated initial CSF shunt placement during this time period. During the 24 months of follow-up, these patients had a total of 825 shunt infections and 4434 subsequent shunt procedures. Overall unadjusted 24-month CSF shunt infection rates were 11.7% per patient and 7.2% per procedure. Unadjusted 24-month cumulative incidence rates for each hospital ranged from 4.1 to 20.5% per patient and 2.5–12.3% per procedure. Factors significantly associated with infection (p < 0.05) included young age, female sex, African-American race, public insurance, etiology of intraventricular hemorrhage, respiratory complex chronic condition, subsequent revision procedures, hospital volume, and surgeon case volume. Malignant lesions and trauma as etiologies were protective. Infection rates for each hospital adjusted for these factors decreased to 8.8–12.8% per patient and 1.4–5.3% per procedure. Conclusions: Infections developed in > 11% of children who underwent uncomplicated initial CSF shunt placements within 24 months. Patient, hospital, and surgeon factors contributed somewhat to the wide variation in CSF shunt infection rates across hospitals. Additional factors may contribute to variation in CSF shunt infection rates between centers, but further study is needed. Benchmarking and future prospective multicenter studies of CSF shunt infection will need to incorporate these and other patient, hospital, and surgeon factors.

Background: Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in the X-linked methyl CpG binding protein 2 (MeCP2) gene. Methods: One hundred sixteen patients with classical and atypical RTT were studied for mutations of the MeCP2 gene by using DHPLC and direct sequencing. Results:Causative mutations in the MeCP2 gene were identified in 63% of patients, representing a total of 30 different mutations. Mutations were identified in 72% of patients with classical RTT and one third of atypical cases studied (8 of 25). The authors found 17 novel mutations, including a complex gene rearrangement found in one individual involving two deletions and a duplication. The duplication was identical to a region within the 3′ untranslated region (UTR), and represents the first report of involvement of the 3′ UTR in RTT. The authors also report the identification of MeCP2 mutations in two males; a Klinefelter’s male with classic RTT (T158M) and a hemizygous male infant with a Xq27-28 inversion and a novel 32 bp frameshift deletion [1154(del32)]. Studies examining the relationship between mutation type, X-inactivation status, and severity of clinical presentation found significant differences in clinical presentation between different types of mutations. Mutations in the amino-terminus were significantly correlated with a more severe clinical presentation compared with mutations closer to the carboxyl-terminus of MeCP2. Skewed X-inactivation patterns were found in two asymptomatic carriers of MeCP2 mutations and six girls diagnosed with either atypical or classical RTT. Conclusion:This patient series confirms the high frequency of MeCP2gene mutations causative of RTT in females and provides data concerning the molecular basis for clinical variability (mutation type and position and X-inactivation patterns).

Osteosarcoma is the most common malignant bone tumor in children. Osteosarcoma patients who respond poorly to chemotherapy are at a higher risk of relapse and adverse outcome. Therefore, it was the aim of this study to identify prognostic factors at the time of diagnosis to characterize the genes predictive of poor survival outcome and to identify potential novel therapeutic targets. Expression profiling of 30 osteosarcoma diagnostic biopsy samples, 15 with inferior necrosis following induction chemotherapy (Huvos I/II) and 15 with superior necrosis following induction chemotherapy (Huvos III/IV), was conducted using Affymetrix U95Av2 oligonucleotide microarrays. One hundred and four genes were found to be statistically significant and highly differentially expressed between Huvos I/II and III/IV patients. Statistically significant genes were validated on a small independent cohort comprised of osteosarcoma xenograft tumor samples. Markers of Huvos I/II response predominantly were gene products involved in extracellular matrix (ECM) microenvironment remodeling and osteoclast differentiation. A striking finding was the significant decrease in osteoprotegerin, an osteoclastogenesis inhibitory factor. Additional genes involved in osteoclastogenesis and bone resorption, which were statistically different, include annexin 2, SMAD, PLA2G2A, and TGFβ1. ECM remodeling genes include desmoplakin, SPARCL1, biglycan, and PECAM. Gene expression of select genes involved in tumor progression, ECM remodeling, and osteoclastogenesis were validated via quantitative reverse transcription-PCR in an independent cohort. We propose that osteosarcoma tumor–driven changes in the bone microenvironment contribute to the chemotherapy-resistant phenotype and offer testable hypotheses to potentially enhance therapeutic response.